Rationale, design, implementation, and baseline characteristics of patients in the dig trial: A large, simple, long-term trial to evaluate the effect of digitalis on mortality in heart failure

Abernathy, G T; Abrams, Jonathan; Akhtar, Shehreen; Al-Bitar, Issam; Amidi, Morteza; Anand, Inder; Jmo., Arnold; Ashton, Thomas; Aubrey, B; Auger, Pierre; Babb, Joseph D.; Baigrie, Ronald S.; Baird, M G; Baitz, T; Barber, N C; Barbour, D J; Barr, Daniel M.; Basu, A K; Baughman, K. L.; Beckham, Valerie; Bekheit-Saad, Soad; Berkson, D M; Bertoglio, M; Bessoudo, Ricardo; Beaudoin, Jonathan; Bhaskar, Gyan; Binder, Andrew; Bloomfield, D; Bodine, K; Boehmer, J P; Borgersen, K; Borts, David J.; Bouchard, Gianna; Bourassa, Martial G.; Boutros, G; Bozek, B; Brisbin, D; Brophy, James M.; Brossoit, R; Brown, Edward J.; Brown, Jim; Bruinsma, Nienke; Burton, Gerardo; Cameron, Alan C.; Campbell, Ross T.; Campeau, Joseph D.; Campos, E E; Cardello, FP; Carter, R P; Chan, YK; Charles, F; Chaudhry, M A; Chiaramida, Anthony J.; Chiaramida, Salvatore A.; Chohan, Asad; Christie, L G; Clemson, B.S; Collin, R; Cook, T H; Copen, D L; Cossett, J; Costantino, Thomas; Crawford, M H; Croke, R P; Crowell, Rebecca; DAmours, G; Dagenais, G. R.; Danisa, Kola; Davidson, Sandra; Davies, M L; Davies, RA; DeLarochellière, Robert; DeLeon, A C; Delage, F; Denes, Pablo; Dennish, GW; Denny, D. Marty; DeVilla, M A; DeYoung, J. Paul; Dhurandhar, R W; Dibner-Dunlap, Mark E.; Dodek, Arthur; Doherty, J E; Jc, Dominguez; Dubbin, James; Dufton, J; Effron, MB; El-Sherif, N; Eladasari, BR; Fly, Deborah; Ericson, Katharina; Fahrenholtz, D; Fast, Angela M.; Fell, D.; Fishman, S; Fitchett, David; Fleg, Jerome L.; Flint, E J; Folger, J S; Folkins, D; Forker, A. D.; Fowles, R E; Fraker, T D; Francis, Gary S.; Frerking, T R; Friesinger, G C; Fulop, J C; Gagnon, Julien; Gamble, L; Ganjavi, F; Garrou, B W; Gervais, P B; Gheorghiade, Mihai; Gilbert, Laura; Gillie, Edward; Glatter, T R; Godley, ML; Goeres, M; Goldberger, M H; Gollapudi, Anurekha; Goode, J E; Goodman, L S; Gordon, RobertS.; Gossard, Denis; Gosselin, Gilbert; Goulet, Claude; Grant, C. S.; Graettinger, W F; Greene, J G; Greenwood, P V; Gregoratos, Gabriel; Gregory, J J; Groden, D L; Grover, John W.; Gudapati, Ramesh; Guess, M A; Gupta, S.C.; Habib, Naomi; Hack, I; Hamilton, W P; Hankey, T L; Hanna, Magdy; Harper, D; Harris, D E; Hassapoyannes, C A; Hatheway, R J; Heinsimer, James A.; Pequignot, M H; Heiselman, DE; Hess, A R; Hickner, John; Hickey, J E; Higgins, Trevor J. C.; Higginson, Lyall; Hill, Loreena; Hobbs, R E; Honos, George; Horner, B A; Horwitz, Leora I.; Hsieh, Alexander; Hsueh, J T; Hubbard, James; Hughes, D.; Hui, William; Imrie,; Jacobs, M H; Jarmukli, Nabil; Johnson, T H; Jutila, C K; Kadri, Nazih; Kahl, F R; Kaimal, P.K.; Karnegis, James N.; Kay, Ronald G.; Kelly, K J; Kenefick, G; Kennelly, BM; Kent, Eleanor; Khan, AH; Khanijo, V; Khouri, Michel G.; Kinloch, David; Kirlin, P C; Kiwan, G S; Kline,; Kohn, R M; Koilpillai, Chris; Kornder, J M; Kouz, Simon; Kumar, V A; Kumar, Uday; Kuntz, Arlene; Kuritzky, R A; Kuruvilla, G; Kwok, K K; Lader, Ellis; Laforest, Marie-Eve; LaForge, David H; Lalonde, Guy; Lalonde, LD; Lang, Ruth; Latour, Y; Lawal, Oluwasola; Leblanc, Marie-Hélène; Lee, A B; Lee, R W; Legault, Claudine; Lemay, Mathieu; Jhf., Lenis; Lepage, Serge; Letarte, Peter B.; Lévesque, Claude; LevinoffRoth, S N; Lewis, B K; Lipshutz, H; Loungani, R R; Lowery, Mark; Lubell, D L; Lucariello, Richard J.; LugoRodriguez, J E; Lui, Chun Tat; Lutterodt, A T; Lutz, Lois; Machel, T; Macina, Gregory; MacLellan, Keith; Magnan, O; Mansuri, Muhammad Fasih; Manyari, D E; Mallis, G.; Marr, D; Mast, D; Mathew, James; McBarron, F D; McIntyre, K M; McLean, R W; McMahon, DP; Mercier, Mariette; Méthé, M; Ab, Miller; Minkowitz, J; Milton, Marilyn Daisy; Mizgala, H F; Mohanty, P K; Mohiuddin, Syed M.; Montero, Anastasio; Mookherjee, S; Morris, Andrew L.; Morris, L; Morrison, J. M.; Moten, Marriyam; Nafziger, Anne N.; Nair, P.; Nawaz, Shah; Neiman, J C; Nutting, Paul A.; NguyenPho, H T; O’Brien, T. K.; OKelly, R L; OReilly, M V; Okerson, D; Patel, Gauravkumar; Pande, P N; Papa, L A; Patrick, Lorna; Payne, R M; Perry, Gilbert J.; Philbin, E.F.; Pierpont, Gordon L.; Pitt, W A; Poirier, Claude; Pollak, E M; Popio, Kenneth A.; Poulin, J F; Probst, Paul; Pruneau, Genevieve M.; Pu, Charles T.; Puram, B S; Putatunda, B; Quinn, Beverly; Rabkin, S.; Racine, Normand; Raco, D L; Radant, L; Radford, MJ; Radwany, Steven; Rajachar, M; Ramanathan, K.; Rashkow, Andrew; Rausch, D C; Read, Laura L.; Reddy, K. Rajender; Reid, R; Rich, M W; Ricci, A; Richman, H G; Riley, Alan; Rim, D A; Rinne, Claus; Roberge, G; Roberts, Diana; Robinson, V.J.; Rodeheffer, R T; Rosenstein, Robert; Roth, D. L.; Rothbart, Robert M.; Rouleau, J L; Ruble, Paul E.; Sacco, Joseph; Safford, R E; Salmon, Daniel A.; Sahay, BM; Sarma, R J; Mar., Sayeed; Schick, E C; Schroeder, G S; Seifert, Michael; Mpj., Senaratne; Sestier, F; Shah, Ami A.; Shanes, J. G.; Sheesley, Karen A.; Silverman, Alan H.; Shiva, T; Shrestha, D D; Silver, M. A.; Silverberg, L; Simard, Louis; Singh, B N; Small, R S; Smith, M. R.; Smith, Stuart A.; Sochowski, R A; Southern, R F; Sridharan, Marandapalli R.; StHilaire, R; Stein, M.; Stewart, J. W.; Stillabower, M E; Bhm., Sullivan; Sturrock, W A; Sussex, B A; Swan, J; Swenson, Lyle; Talbot, Paul; Talibi, T; Tamilia, Michael; Tan, Audrey R; Tanser, P H; Tarry, L; Teo, Koon K.; Thadani, Udho; Thagirisa, S; Thompson, Brenda; Thornton, Ruth B.; Timmis, G C; Tobin, M.; Tommaso, Cristina Di; Toren, Michael; Tsuyuki, Ross T.; Turek, Michèle; Utley, K; Vanderbush, E.J.; VanVoorhees, Lucy; Ventura, Héctor O.; Vértes, Gergely; Vizel, Saul; Wagner, KR; Wagner, Ştefan; Weeks, A. M.; Weingert, M E; Weinstein, Cheryl E.; Weiss, M; Weiss, Robert G.; Wickemeyer, W. J.; Wielgoz, A; Willens, H. J.; Williams, W L; Wong, Douglas; Yarows, S A; Yao, Louis; Shalev, Yoseph; Young, J. B.; Yousefian, Mahzad; Zajac, E J; Zatuchni, Jacob; Ziperman, D B; Zoble, RG; Zoneraich, Samuel; Gorlin, Richard; Sleight, Peter; Cohn, Jay N.; Collins, Rory; Deykin, Daniel; Hennekens, C; Kjekshus, John; Smith, T W; Tognoni, Gianni; Collins, Joseph F.; Williford, William O.; Fye, Carol L.; Sather, R; Jolly, M. King; Held, Claes; Verter, Joel; Yusuf, Salim; Egan, Debra; Garg, Rekha; Johnstone, D E; Montague, Terrence J.; Bristow, DG; Engelhardt, H. Tristram; Gent, Michael; Hood, William B.; Jones, Siân; Meier, Paul; Pitt, Bertram; Waters, David D.; Baker, Albert; Barnhill, S; Carew, Beryl; Hagar, S; Liuni, C; Martin, Sylvia; Miles, Rodney R.; Arthur, M M; Feldbush, M W; Highfield, David; Hobbins, Thomas E.; Kurz, R; Leviton, S P; Libonati, J P; Moore, Meredith; Pérez, Eduardo; Mills, P. G.; Geller, Nancy L.; Hunsberger, Sally; Gold, Jonathan W. M.; Huang, Pingping; Burns, Andrew; Caleb, Harrell; Cline,; Harris, Steven C.; Hockenbrock, R; Horney, Rebecca A.; Jadwin, L M; King, James F.; Sexton, Paul; Spence, Marisha; Chacon, F; Gagne, William H.; Maple, S; Martínez, Guillermo Oller

doi:10.1016/0197-2456(95)00065-8

Cited by 120 publications

(2 citation statements)

References 21 publications

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“…Based on the DIG and RATE-AF data, treatment with digoxin within serum concentrations below 1.0 ng/ml seems to be safe in patients with heart failure and/or AF [3,5]. In the DIG [15,16]. However, no data are available in patients with HFrEF demonstrating the relationship between digitoxin dose and blood concentrations.…”

Section: Discussionmentioning

confidence: 99%

Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial

et al. 2023

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Background The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial. Methods and results In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5–23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m2, and BMI < 27 kg/m2 each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively. Conclusion In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m2, BMI < 27 kg/m2, or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial

et al. 2023

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“…In 2003, Rathore et al, evaluated the association of digoxin level and mortality in patients with heart failure by performing a post hoc analysis of the 1991-1995 DIG trial (45,46). In the DIG trial, a double-blinded placebo trial, men with heart failure were randomized to either placebo (n = 2,639) or digoxin (n = 2,642) with the intent of achieving a serum digoxin concentration of 0.5-2.0.…”

Section: The Digoxin Therapeutic Range and Reported Risk Of Mortalitymentioning

confidence: 99%

Review: Failure of current digoxin monitoring for toxicity: new monitoring recommendations to maintain therapeutic levels for efficacy

Gona,

Rosenberg,

Fyffe-Freil

et al. 2023

Front. Cardiovasc. Med.

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The current recommendations for monitoring digoxin, a narrow therapeutic index drug, are limited to confirming medication use or investigating suspicion of toxicity and fail our oath to do no harm. Numerous meta-analyses evaluating digoxin use consistently recommend frequent monitoring to maintain the level of 0.5 to ≤1.0 ng/ml because higher levels lead to increased morbidity and mortality without benefit. Data from the United States National Poison Control Center (2012–2020) show annual deaths due to digoxin of 18–36 compared to lithium's 1–7, and warfarin's 0–2 respectively. The latter drugs also have narrow therapeutic indexes like digoxin yet are more carefully monitored. Recognition of digoxin toxicity is impaired as levels are not being routinely checked after medications are added to a patient's regimen. In addition, providers may be using ranges to guide treatment that are no longer appropriate. It is imperative that monitoring guidelines and laboratory therapeutic levels are revised to reduce morbidity and mortality due to digoxin. In this review, we provide a comprehensive literature review of digoxin monitoring guidelines, digoxin toxicity, and evidence to support revising the ranges for serum digoxin monitoring.

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The Relationship Between Cardiothoracic Ratio and Left Ventricular Ejection Fraction in Congestive Heart Failure

Philbin

Garg²,

Danisa³

et al. 1998

Arch Intern Med

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Rationale, design, implementation, and baseline characteristics of patients in the dig trial: A large, simple, long-term trial to evaluate the effect of digitalis on mortality in heart failure

Cited by 120 publications

References 21 publications

Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial

Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial

Review: Failure of current digoxin monitoring for toxicity: new monitoring recommendations to maintain therapeutic levels for efficacy

The Relationship Between Cardiothoracic Ratio and Left Ventricular Ejection Fraction in Congestive Heart Failure

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